The T cell immunoglobulin and mucin domain (Tim) family of proteins have important and broad immune functions. Of these family members, Tim-1 was first identified to be expressed on activated CD4+ T cells and regulates Th2 responses and Th2-driven airway hyper-sensitivity. We and others have shown that manipulating Tim-1 signaling also regulates experimental autoimmune encephalomyelitis (EAE) and allogeneic transplant tolerance via mediating the development and/or function of Th1, Th17 and Treg cells. Almost all functional data on the biology of Tim-1 in T cells in these studies were obtained using different anti-Tim-1 antibodies that were either analyzed in vitro in the presence of antigen-presenting cells (APCs) or in vivo in animal models of the above mentioned diseases. I have recently found that Tim-1 is constitutively expressed on dendritic cells (DCs). I have also generated Tim-1 knockout mice and my preliminary data indicates that loss of Tim-1 affects both DC function and T cell responses. Because DCs play a central role in regulating T cell responses, my preliminary data suggests that the different T cell responses observed in previous studies may be due to the effect of Tim-1 on T cells or DCs, or both. Studies have suggested that both CD4+ T cells and DCs play key roles in the pathogenesis of colitis. However, whether Tim-1 plays a role in the pathogenesis of colitis is not known. Therefore, I will utilize Tim-1 knockout mice to systematically analyze the role of Tim-1 in regulating CD4+ T cell and DC responses and the development of colitis in animal models. The proposed study will advance our understanding of Tim-1 in immune regulation, which will have important implications for the development of novel therapeutic strategies for autoimmune diseases and chronic inflammatory conditions. PUBLIC HEALTH RELEVANCE: Autoimmune disease is caused by a dysregulated immune response. Tim-1 is a cell surface molecule expressed on immune cells and plays an important role in regulating immune responses. Here, I propose to study the effect and mechanism of Tim-1 in regulating immune responses and autoimmune diseases. Our ultimate goal is to determine whether Tim-1 could be targeted therapeutically for the treatment of autoimmune diseases.